Use of methylnaltrexone and related compounds

ABSTRACT

A method for preventing or treating the opioid induced side effect, inhibition of gastrointestinal motility is disclosed. The method comprises administering methylnaltrexone or another quaternary derivative of noroxymorphone to a patient prior to the administration of an opioid or after the onset of side effects induced by the administration of an opioid, wherein the methylnaltrexone or quaternary derivative is administered orally in an enterically coated form.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 08/962,742, filedNov. 3, 1997, now U.S. Pat. No. 5,972,954, the disclosure of which isherein incorporated by reference.

Partial funding of the work described herein was provided under M01RR00055 awarded by the U.S. Public Health Service General ClinicalResearch Center, and the U.S. Government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention is directed at the treatment of certain sideeffects associated with the use of opioids as analgesics. In particularthe present invention is directed at treating opioid-induced inhibitionof gastrointestinal motility and constipation.

BACKGROUND OF THE INVENTION

Opioids are effective analgesics. However, their use is associated witha number of undesirable side effects. One such effect is constipation.Opioid-induced changes in gastrointestinal motility are almost universalwhen these drugs are used to treat pain, and at times may limit theiruse, leaving the patient in pain. Common treatments of bulking agentsand laxatives have limited efficacy and may be associated with sideeffects such as electrolyte imbalances.

One treatment for opioid side effects is the use of opioid antagonistswhich cross the blood-brain-barrier, or which are administered directlyinto the central nervous system. Opioid antagonists such as naltrexoneand naloxone have been administered intramuscularly or orally to treatopioid induced side effects. Naltrexone and naloxone are highly lipidsoluble and rapidly diffuse across biological membranes, including theblood-brain barrier. However, naltrexone, naloxone, nalmefene, and otheropioid antagonists which may reverse many opioid side effects have anarrow therapeutic window before they are observed to reverse thedesired analgesic effect of the opioid being used.

Many quaternary amine opioid antagonist derivatives, such asmethylnaltrexone, do not reduce the analgesic effect of opioids. Thesequaternary amine opioid antagonist derivatives, which have a relativelyhigher polarity and reduced lipid solubility when compared to thetertiary forms of the drugs, were specifically developed to not traversethe blood-brain barrier or to traverse it at a greatly reduced rate.However, high levels of MNTX in the plasma can lead to undesirable sideeffects such as orthostatic hypotension.

It is desirable in the treatment of many conditions to have oralmedications with prolonged effects. Such oral medications areparticularly desirable for the treatment of opioid-induced side effects.

It is further desirable to develop a method for the prevention ofopioid-induced inhibition of gut motility and constipation which doesnot counteract the analgesic effects of the opioid, or risk increasedlevels of pain. Ideally, such a treatment has few side effects eitherdue to low drug toxicity or because administration of small amounts areeffective and/or administration results in low circulating levels of thedrug.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is a graph representing plasma concentrations of MNTX followingadministration of 6.4 mg/kg of uncoated MNTX.

FIG. 1B is a graph representing plasma concentrations of MNTX followingadministration of 6.4 mg/kg of enterically coated MNTX.

FIG. 1C is a graph representing plasma concentrations of MNTX followingadministration of 3.2 mg/kg of enterically coated MNTX.

FIG. 2 illustrates the reversal of morphine's effect on oral-cecaltransit time following administration of 6.4 mg/kg of uncoated MNTX. Thedarker line represents the average of all points of a given treatment.

FIG. 3 illustrates the reversal of morphine's effect on oral-cecaltransit time and its decrease below baseline following administration of6.4 mg/kg of enterically coated MNTX. The darker line represents theaverage of all points of a given treatment.

FIG. 4 illustrates the reversal of morphine's effect on oral-cecaltransit time following administration of 3.2 mg/kg of enterically coatedMNTX. The darker line represents the average of all points of a giventreatment.

SUMMARY OF THE INVENTION

The present invention is directed at methods for preventing and treatingopioid-induced inhibition of gut motility and constipation.

The method for preventing opioid-induced decreased gut motility andconstipation comprises administering enterically coated methylnaltrexoneor other quaternary derivatives of noroxymorphone as disclosed in U.S.Pat. No. 4,176,186 to Goldberg et al. (herein incorporated by reference)to a patient prior to or simultaneously with the administration of anopioid.

The method for treating opioid-induced inhibition of gut motility andconstipation comprises administering enterically coated methylnaltrexoneor other quaternary derivatives of noroxymorphone to a patient after theonset of the side effect.

DETAILED DESCRIPTION

The present invention is directed to methods for preventing and treatingopioid-induced constipation and changes in gut motility via the oraladministration of an enteric coated quaternary derivatives ofnoroxymorphone (QDNM), particularly methylnaltrexone (MNTX).Administration of non-enterically coated MNTX results in rapidabsorption of MNTX through the stomach and early peak and sustained highlevels of MNTX in the plasma. However, an enteric coating on the QDNM,designed to prevent dissolution and subsequent absorption of the drug inthe stomach, would be expected to produce delayed elevation of plasmalevels of the QDNM, and to produce a lower peak plasma level.Suprisingly, however, administration of enterically coated MNTX has beenfound to result in substantially lower plasma levels as compared tonon-enterically coated MNTX at the same dosage level, and surprisinglyand unexpectedly resulted in enhanced efficacy in the reversal ofopioid-induced decreases in gastrointestinal motility. In fact, it hasbeen found that as compared to non-enterically coated MNTX, asignificantly lower dose, e.g., less than half the amount of coated MNTXcan be used if enterically coated to achieve the same levels of reliefof opioid-induced constipation. Moreover, such reduced dosage levels ofMNTX administered with an enteric coating results in exceedingly lowpeak and sustained plasma levels of MNTX, greatly reducing the potentialadverse side effects of the MNTX. This novel improvement in the clinicalindication for use of MNTX has led to an increased therapeutic index forthis drug.

When used as a treatment for the opioid- and nonopioid-induced sideeffects of constipation and reduction of gastrointestinal motility,orally administered, particularly if enterically coated, MNTX or otherquaternary derivatives of noroxymorphone provide prolonged relief of theside effects. MNTX has been demonstrated to have the ability to blockthe gastrointestinal effects of opioids on motility when administeredintravenously or orally. The oral administration of non-entericallycoated MNTX is associated with plasma levels with an early peak (20 min)and prolonged presence (half-life of about 3 hours after single dose of6.4 mg/kg).

Furthermore, for treatment or prevention of constipation and delayedgastrointestinal emptying, whether caused by extrinsic or endogenousopioids, enteric coating surprisingly allows for equal or betterefficacy despite lower plasma levels. Idiopathic constipation, i.e.,that due to causes other than exogenous administration of opioids, maybe mediated by opioid sensitive mechanisms. Endogenous opioid receptorshave been identified in the gut, and these receptors may modulate gutmotility. Thus, administration of an opioid antagonist with peripheralaction, such a methylnaltrexone or other quaternary derivatives ofnoroxymorphone, would block the effects of endogenous opioids.

Quaternary derivatives of noroxymorphone are described in full inGoldberg et al., (supra), and in general are represented by the formula:

wherein R is allyl or a related radical such as chlorallyl,cyclopropyl-methyl or propargyl, and X is the anion of an acid,especially a chloride, bromide, iodide or methylsulfate anion.

The presently preferred quaternary derivative of noroxymorphone ismethylnaltrexone. Methylnaltrexone is a quaternary amine derivative ofnaltrexone. Methylnaltrexone has been found to have only 2 to 4% of theopiate antagonistic activity of naltrexone in vivo due to its inabilityto pass the blood-brain-barrier and bind to the opiate receptors in thecentral nervous system.

Opioids are typically administered at a morphine equivalent dosage of:0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kgbody weight for intramuscular administration; 0.05 to 1.0 mg/kg bodyweight/hour for transmucosal or transdermal administration. By “morphineequivalent dosage” is meant representative doses of other opioids whichequal one milligram of morphine, for example 10 mg meperidine, 1 mgmethadone, and 80 μg fentanyl.

In accordance with the present invention, methylnaltrexone isadministered at a dosage of: 0.1 to 40.0 mg/kg body weight for oraladministration, including enteric coated methylnaltrexone.

The administration of the methylnaltrexone is preferably commenced priorto administration of the opioid to prevent opioid-induced inhibition ofgastrointestinal motility or constipation. It is desirable to commenceinternal administration of methylnaltrexone about 20 minutes prior toadministration of opioids in order to prevent these opioid-induced sideeffects. While the prevention of symptoms is preferred, methylnaltrexoneadministration may also be commenced after the administration of theopioid or after the onset of opioid induced symptoms as a treatment forthose symptoms.

Methylnaltrexone is rapidly absorbed after oral administration from thestomach and bowel. Initial plasma levels of the drug are seen within5-10 minutes of the administration of non-enteric coated compound.Addition of an enteric coating which prevents gastric absorption isassociated with lower plasma levels of the methylnaltrexone.Surprisingly, the addition of an enteric coating (i.e., a coating whichwill prevent degradation or release in the stomach, but will releasedrug in the small and large bowel) enhances the efficacy ofmethylnaltrexone in the prevention of decreases in gut motility byintravenously administered opioids (morphine).

In a preferred embodiment for the prevention and/or treatment ofconstipation and inhibition of gastrointestinal motility, the QDNM orMNTX is enterically coated and administered orally. For oraladministration, the QDNM or methylnaltrexone is formulated withpharmacologically acceptable binders to make a tablet or capsule with anenteric coating. An enteric coating is one which remains intact duringpassage through the stomach, but dissolves and releases the contents ofthe tablet or capsule once it reaches the small intestine. Mostcurrently used enteric coatings are those which will not dissolve in lowpH environments, but readily ionize when the pH rises to about 4 or 5,for example synthetic polymers such as polyacids having a pK_(a) of 3 to5.

The enteric coating may be made of any suitable composition. Suitableenteric coatings are described, for example, in U.S. Pat. No. 4,311,833to Namikoshi, et al.; U.S. Pat. No. 4,377,568 to Chopra; U.S. Pat. No.4,385,078 to Onda, et al.; U.S. Pat. No. 4,457,907 to Porter; U.S. Pat.No. 4,462,839 to McGinley, et al.; U.S. Pat. No. 4,518,433 to McGinley,et al.; U.S. Pat. No. 4,556,552 to Porter, et al.; U.S. Pat. No.4,606,909 to Bechgaard et al.; U.S. Pat. No. 4,615,885 to Nakagame, etal.; U.S. Pat. No. 4,670,287 to Tsuji; U.S. Pat. No. 5,536,507 toAbramowitz, et al.; U.S. Pat. No. 5,567,423 to Ying, et al.; U.S. Pat.No. 5,591,433 to Michael, et al.; U.S. Pat. No. 5,597,564 to Ying, etal.; U.S. Pat. No. 5,609,871 to Michael, et al.; U.S. Pat. No. 5,614,222to Kaplan; U.S. Pat. No. 5,626,875 to Rodes, et al.; and U.S. Pat. No.5,629,001 to Michael, et al., all of which are incorporated herein byreference.

Preferred enteric coating compositions include alkyl and hydroxyalkylcelluloses and their aliphatic esters, e.g., methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxybutylcellulose, hydroxyethylethylcellulose,hydroxyprophymethylcellulose, hydroxybutylmethylcellulose,hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalateand hydroxypropylmethylcellulose acetate succinate;carboxyalkylcelluloses and their salts, e.g.,carboxymethylethylcellulose; cellulose acetate phthalate; celluloseacetate trimellitate, polycarboxymethylene and its salts andderivatives; polyvinyl alcohol and its esters: polyvinyl acetatephthalate; polycarboxymethylene copolymer with sodium formaldehydecarboxylate; acrylic polymers and copolymers, e.g., methacrylicacid-methyl methacrylic acid copolymer and methacrylic acid-methylacrylate copolymer; edible oils such as peanut oil, palm oil, olive oiland hydrogenated vegetable oils; polyvinylpyrrolidone; polyethyleneglycol and its esters; natural products such as shellac, and zein.

Other preferred enteric coatings include polyvinylacetate esters, e.g.,polyvinyl acetate phthalate; alkyleneglycolether esters of copolymerssuch as partial ethylene glycol monomethylether ester ofethylacrylate-maleic anhydride copolymer or diethyleneglycolmonomethylether ester of methylacrylate-maleic anhydride copolymer,N-butylacrylate-maleic anhydride copolymer, isobutylacrylate-maleicanhydride copolymer or ethylacrylate-maleic anhydride copolymer; andpolypeptides resistant to degradation in the gastric environment, e.g.,polyarginine and polylysine. Other suitable coatings and methods to makeand use such formulations are well known to those skilled in the art(see, e.g., Remington: The Science and Practice of Pharmacy, 19th ed.(1995) Mack Publishing Company, Easton, Pa.; herein incorporated byreference).

Mixtures of two or more of the above compounds may be used as desired.The presently preferred enteric coating comprises cellulose acetatephthalate.

The enteric coating material may be mixed with various excipientsincluding plasticizers such as triethyl citrate, acetyl triethylcitrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyltartrate, dibutyl maleate, dibutyl succinate and diethyl succinate andinert fillers such as chalk or pigments.

The composition and thickness of the enteric coating may be selected todissolve immediately upon contact with the digestive juice of theintestine. Alternatively, the composition and thickness of the externalcoating may be selected to be a time-release coating which dissolvesover a selected period of time, as is well known in the art.

The amount of enteric coating depends on the particular enteric coatingcomposition used and is preferably sufficient to substantially preventthe absorption of MNTX in the stomach.

Hydroxyalkyl celluloses and their aliphatic esters, carboxyalkylcelluloses and their salts, polycarboxymethylene and its salts andderivatives, polyvinyl alcohol and its esters, polycarboxymethylenecopolymer with sodium formaldehyde carboxylates, poly-vinylpyrrolidone,and polyethylene glycol and its esters can be applied as entericcoatings by first dissolving the compound in a minimum amount of water.Alcohol is then added to the point of incipient cloudiness. The mixturecan then be applied by conventional techniques.

Application of cellulose acetate phthalate may be accomplished by simplydissolving the cellulose acetate phthalate in a minimum amount ofalcohol and then applying by conventional techniques. Hydrogenatedvegetable oils may be applied by first dissolving the oil in a minimalamount of a non-polymer solvent, such as methylene chloride, chloroformor carbon tetrachloride, then adding alcohol to the point of incipientcloudiness and then applying by conventional techniques.

In a particularly preferred embodiment, the MNTX is coated with EudragitL100 or S100, a methacrylic acid copolymer enteric coating, at a 50%coating level to provide stability at gastric pH and dissolution at gutpH per a US Pharmacopeia (USP) standard for enteric coatings.

In the above description, methylnaltrexone is used as an example of aparticularly effective QDNM. It is apparent that other QDNM's may beused as desired.

The following Examples are intended to illustrate aspects of theinvention and are not to be construed as limitations upon it. Themethylnaltrexone used in the following Examples was manufactured byMallinckrodt Pharmaceuticals, St. Louis, Mo. The Enteric Coating wasmanufactured by Coating Place, Inc., Verona, Wis.

EXAMPLE 1 Effects Of Enterically Coated MNTX On Oral-Cecal Transit Timeand Plasma Levels of MNTX

Oral methylnaltrexone, whether enterically coated or uncoated, was shownto reverse the inhibitory effects of opioid administration ongastrointestinal motility as measured by oral-cecal transit time. Ascompared to non-enterically coated MNTX, however, treatment withenterically coated MNTX enhanced the efficacy of the drug at a lowerdose while producing lower plasma levels of MNTX.

Subjects were divided into five treatment groups A-E. With the exceptionof subjects in Group A, who were given a placebo in place of morphine,all were given an intravenous dose of morphine at 0.05 mg/kg. Prior tomorphine administration, subjects were given either a placebo or MNTX invarious doses and formulations (see Table 1). The subjects in Group Aand B were given a placebo in place of MNTX. Group C received uncoatedMNTX at 6.4 mg/kg, Group D received enterically coated MNTX at 6.4 mg/kgactive drug, and Group E received enterically coated MNTX at 3.2 mg/kgactive drug. Table 1 shows the treatments for each group.

TABLE 1 Group Treatment combination FIG. A placebo placebo B morphineplacebo (0.05 mg/kg) C morphine methylnaltrexone uncoated FIG. 2 (0.05mg/kg) (6.4 mg/kg) D morphine methylnaltrexone enteric coated FIG. 3(0.05 mg/kg) (6.4 mg/kg active drug) E morphine methylnaltrexone entericcoated FIG. 4 (0.05 mg/kg) (3.2 mg/kg active drug)

Plasma levels of MNTX were measured following administration of morphineand MNTX or placebo several times over the duration of the six hourmonitoring period, at the times shown in FIG. 1. Measurements of plasmaand urine MNTX levels were determined by high performance liquidchromatography (HPLC) using the modified method originally reported byKim et al. (1989) Chromatographia 28:359-63, herein incorporated byreference). Methylnaltrexone was separated from plasma by solid phaseextraction (SPE). Plasma samples (100-500 μl ) diluted in water with theinternal standard (naltrexone) were passed through SPE columns. Prior touse, the columns were conditioned by methanol and washed with water. Theanalytes were eluted from the columns by the mixture of n-propanol andtrifluoroacetic acid (25 mM) aqueous solution prepared in 2:1proportion. The eluate was evaporated to dryness in a stream of nitrogenat 55° C. The residue was reconstituted in the mobile phase, filteredthrough a nylon HPLC syringe filter and subjected to HPLC analysis. AShimadzu Corporation (Kyoto, Japan) HPLC system was used. It consistedof the LC-10AD pump, SCL-10A system controller, and SIL-10A autoinjector equipped with sample cooler. Used HPLC Analytical Column madeby Phenomenex (Prodigy C8, Torrance, Calif.). The electrochemicaldetector (ESA Coulochem, model 5100A) worked at the following settings:detector 1, +360 mV, detector 2 +600 mV, guard cell +650 mV. Data werecollected with the use of EZChrom 2—2 HPLC software. The mobile phaseconsisted of 50 mM sodium acetate, 7.5% methanol at pH 4.2. The systemwas calibrated daily in the range of 5-100 ng/ml (3 point calibration).Practical limit of detection for plasma samples was approximately 2ng/ml (100 pg/injection).

FIG. 1 shows the plasma levels of MNTX following the treatments inGroups C, D, and E. In FIG. 1A, MNTX plasma levels in Group C (given 6.4mg/kg MNTX, uncoated) peaked at about 15 min. post-MNTX administrationand remained at a roughly constant level (between about 35-50 ng/ml) forthe duration of the study period (6 hours). Group D, given 6.4 mg/kgMNTX in an enterically coated formulation, exhibited a constant lowplasma level of MNTX (under 10 ng/ml) for the duration of observation(see FIG. 1B). Group E, given 3.2 mg/kg MNTX in an enterically coatedformulation, showed plasma levels of MNTX over the course of observationthat were undetectable or at the lower limit of detection of the assay(see FIG. 1C).

Oral-cecal transit time was used as a measure of gut motility andpropensity for constipation. Oral-cecal transit time was measured by thelactulose-breath hydrogen method. Group A demonstrated normal transittimes as previously described in the literature (Yuan et al. (1996)Clin. Pharmacol. Ther. 59:469-475; Yuan et al. (1997) Clin. Pharmacol.Ther. 61:467-475). Group B had prolongation of their oral-cecal transittimes by 50-100%, while Groups C (FIG. 2) and E (FIG. 4) had theirtransit times return to baseline levels. Group D showed an obviousdecrease in oral-cecal transit time (FIG. 3).

As demonstrated in FIGS. 1-4, enterically coated MNTX provides thetherapeutic effects on gastrointestinal motility of uncoated MNTX, butrequires a lower dose of active drug and results in significantlyreduced plasma levels of MNTX. Patients provided with a dose of 6.4mg/kg of uncoated MNTX had gut motility return to baseline followingmorphine administration (FIG. 2) and showed plasma MNTX levels of over40 ng MNTX/ml, while patients given the same dose in an entericallycoated formulation showed oral-cecal transit times below baseline levels(FIG. 3) and plasma MNTX levels under 10 ng/ml. Enterically coatedformulations of MNTX with one half the dose of active drug (3.2 mg/kg)were required to return oral-cecal transit times to I 5 normal withoutincreasing gut motility. At this dosage, plasma levels of MNTX werenegligible.

As with most drugs, it is desirable to maintain the lowest possiblesystemic levels of MNTX which are sufficient to provide the desiredtherapeutic effect. For example, elevated circulating levels of MNTX canresult in orthostatic hypotension. The present discovery provides anunexpected means to avoid such undesirable drug side effects by loweringthe dose administered and subsequently minimizing circulating levels ofthe drug. Since endogenous and externally supplied opioid-inducedinhibition of gastrointestinal motility and constipation is thought toresult from opioid receptors located within the gastrointestinal tract,enterically coated MNTX or other QDNMs may provide a localadministration of the drug that does not require a circulating level foreffective prevention or treatment of symptoms. Thus, the amount and/orfrequency of drug administered can be reduced.

The preceding description and Examples are intended to be illustrative.Those skilled in the art to which the invention pertains will appreciatethat alterations and changes in the described protocols may be practicedwithout departing from the meaning, spirit, and scope of this invention.Therefore, the foregoing description should be read consistent with andas support to the following claims, which are to have their fullest andfair scope.

What is claimed is:
 1. A method for preventing opioid induced inhibitionof gastrointestinal motility comprising orally administering anenterically coated quaternary derivative of noroxymorphone to a patientprior to administration of an opioid, wherein substantially noquaternary derivative is released in the stomach.
 2. The method of claim1 wherein the quaternary derivative is methylnaltrexone.
 3. The methodof claim 2 wherein the methylnaltrexone is administered at a dosage a0.1 to 40.0 mg of active drug per kg body weight.
 4. The method of claim3 wherein the methylnaltrexone is administered orally at a dosage ofabout 0.1 to about 10 mg/kg body weight.
 5. The method of claim 2wherein the methylnaltrexone is administered as an enterically coatedtablet or capsule, or as enterically coated granules.
 6. The method ofclaim 2 wherein the patient's plasma level of methylnaltrexone remainsbelow 25 ng/ml.
 7. The method of claim 2 wherein the enteric coatingprovides time release of the methylnaltrexone.
 8. The method of claim 1wherein the inhibition of gastrointestinal motility is manifested asconstipation.
 9. The method of claim 1 wherein the patient's peak andsustained plasma levels of the quaternary derivative are below about 50ng/ml.
 10. The method of claim 1, wherein the patient's peak bloodplasma levels are lower than they would be if 10% or more of the samedose of quaternary derivative were released in the stomach and the restwas released enterically.
 11. A method for treating opioid inducedinhibition of gastrointestinal motility comprising orally administeringan enterically coated quaternary derivative of noroxymorphone to apatient subsequent to administration of an opioid, wherein substantiallyno quaternary derivative is released in the stomach.
 12. The method ofclaim 11 wherein the quaternary derivative is methlynaltrexone.
 13. Themethod of claim 12 wherein the patient's plasma level ofmethylnaltrexone remains below 25 ng/ml.
 14. The method of claim 12wherein the methylnaltrexone is administered at a dosage 0.1 to 40.0 mgof active drug per kg body weight.
 15. The method of claim 14 whereinthe methylnaltrexone is administered orally at a dosage of about 0.1 toabout 10 mg/kg body weight.
 16. The method of claim 12 wherein themethylnaltrexone is administered as an enterically coated tablet orcapsule, or as enterically coated granules.
 17. The method of claime 12wherein the enteric coating provides time release of themethylnaltrexone.
 18. The method of claim 11 wherein the inhibition ofgastrointestinal motility is manifested as constipation.
 19. The methodof claim 11 wherein the patient's peak and sustained plasma levels ofthe quaternary derivative are below about 50 ng/ml.
 20. The method ofclaim 11, wherein the patient's blood plasma levels are lower than theywould be if 10% or more of the same dose of quaternary derivative werereleased in the stomach and the rest was released enterically.
 21. Amethod for treating opioid induced inhibition of gastrointestinalmotility comprising orally administering an enterically coatedquaternary derivative of noroxymorphone to a patient wherein theinhibition of gastrointestinal motility is induced by endogenousopioids.
 22. A composition for preventing or treating opioid inducedinhibition of gastrointestinal motility comprising an enterically coatedquaternary derivative of noroxymorphone, which is substantially free ofnon-enterically coated quaternary derivative of noroxymorphone.
 23. Acomposition as claimed in claim 22 in the form of a pill, tablet,capsule or granules.
 24. A composition as claimed in claim 22 where thequaternary derivative of noroxymorphone is methylnaltrexone.
 25. Amethod of treating or preventing opioid induced inhibition ofgastrointestinal motility comprising orally administering an entericallycoated quaternary derivative of noroxymorphone to a patient wherein thepatient's peak plasma levels of the quaternary derivative do not exceedabout 50 ng/ml.
 26. The method of claim 25 wherein the patient's peakplasma levels of the quaternary derivative do not exceed about 40 ng/ml.27. The method of claim 25 wherein the patient's peak plasma levels ofthe quaternary derivative do not exceed about 30 ng/ml.
 28. The methodof claim 25 wherein the patient's peak plasma levels of the quaternaryderivative do not exceed about 20 ng/ml.
 29. The method of claim 25wherein the patient's peak plasma levels of the quaternary derivative donot exceed about 10 ng/ml.
 30. The method of claim 25 wherein thepatient's peak plasma levels of the quaternary derivative do not exceedabout 2 ng/ml.